Immune responses must be tightly regulated to avoid hypo-responsiveness on one hand or excessive inflammation and the development of autoimmunity (hyper-responsiveness) on the other. This balance is at least partially attained through the throttling of activating signals by inhibitory signals. This ideally leads to an adequate immune response against an invader without excessive and extended inflammatory signals that promote the development of autoimmunity. The CD94/NKG2 family of receptors is composed of members with activating or inhibitory potential. These receptors are expressed predominantly on NK cells and a subset of CD8+ T cells, and they have been shown to play an important role in regulating responses against infected and tumorigenic cells. Our studies explore all aspects of the biology of these receptors, including ligand and receptor interaction, signaling, membrane dynamics, and regulation of gene expression.Our current emphasis is to understand, at the cell biology and molecular levels, how the the CD94/NKGA inhibitory receptor inactivates signals generated by activation receptors in a dominating manner and by what mechanism this receptor traffics so as to maintain constant presence on the cell surface. This is an intriguing question because CD94/NKG2A is under constant exposure to ligand, which normally leads to receptor down regulation. If this were to happen, NK cells would become hyper-reactive leading to autoimmunity. We have preliminary data showing that CD94/NKG2A traffics by a novel mechanism. We also have preliminary data showing CD94/NKG2A inactivates activation receptors by inactivating key molecules necessary for transmission of activation siganals. It does this in a localized manner so that NK cells can still kill harmful bystander cells at sites where inhibitory signals are not generated. Understanding how CD94/NKG2A receptors signals and maintains cell surface expression are major areas of investigation. Furthermore, understanding the regulation of expression of the CD94 and NKG2A genes is particularly important, as expression of this inhibitory receptor on CD8 T cells has been shown to render these cells anergic. This has been demonstrated for HIV reactive CTLs. A second major area of interest are studies on the NKG2D activation/co-receptor that is expressed on NK and majority of CD8+ T cells. When NKG2D engages ligands (of which there are many) cell signaling events are transmitted through the adapters DAP10 and DAP12, which leads to cell activation events ending in target cell lysis/and or cytokine secretion. This receptor system has been shown to have potential impact in many diseases. Normal cells do not express NKG2D ligands, but cells under stress, i. e. infected and malignant, up-regulate NKG2D ligands making them vulnerable to attack by cells expressing NKG2D. On the negative side, inappropriate expression of NKG2D ligands has been shown to foster autoimmune diseases, such as diabetes, celiac disease, and preliminary evidence suggests a role for NKG2D in other autoimmune diseases. Also therapeutic NKG2D blockade may be of use in transplantation settings. Thus gaining knowledge of the mechanisms mediating the regulation of NKG2D protein and gene expression is an important aim of our research.